Effects of fasudil, a Rho-kinase inhibitor, on myocardial preconditioning in anesthetized rats

Eur J Pharmacol. 2005 Dec 19;527(1-3):129-40. doi: 10.1016/j.ejphar.2005.10.018. Epub 2005 Nov 22.

Abstract

The aim of this study was to examine the effects of fasudil, a Rho-kinase inhibitor, on ischemic preconditioning and carbachol preconditioning in anesthetized rats. The total number of ventricular ectopic beats was markedly augmented with fasudil at 0.3 mg/kg and depressed with fasudil at 10 mg/kg. Fasudil at 10 mg/kg also markedly decreased the ventricular tachycardia incidence. Ischemic preconditioning, induced by 5 min coronary artery occlusion and 5 min reperfusion, decreased the incidence of ventricular tachycardia and abolished the occurrence of ventricular fibrillation. The incidences of ventricular tachycardia and ventricular fibrillation in the fasudil (10 mg/kg) + ischemic preconditioning group were found to be similar to the ischemic preconditioning group. However, low doses of fasudil (0.3 and 1 mg/kg) appeared to prevent the antiarrhythmic effects of ischemic preconditioning. Carbachol (4 microg/kg/min for 5 min) induced marked reductions in mean arterial blood pressure, heart rate and abolished ventricular tachycardia. Marked reductions in ventricular ectopic beats and ventricular tachycardia were noted in the fasudil (10 mg/kg) + carbachol preconditioning group. Lactate levels were markedly reduced in the ischemic preconditioning group and this reduction was prominently inhibited with fasudil at 1 mg/kg. Ischemic preconditioning caused a marked decrease in plasma malondialdehyde levels. Fasudil (10 mg/kg), ischemic preconditioning and carbachol preconditioning each generated marked reductions in ischemic myocardial malondialdehyde levels. Decreases in infarct size were observed with fasudil (10 mg/kg) treatment, ischemic preconditioning and carbachol preconditioning when compared to control. These results suggest that low doses of fasudil (0.3 and 1 mg/kg) appeared to prevents the effects of ischemic preconditioning and carbachol preconditioning, but a high dose of fasudil (10 mg/kg) was able to produce cardioprotective effects on myocardium against arrhythmias, infarct size or biochemical parameters and mimic the effects of ischemic preconditioning in anesthetized rats.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives*
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / therapeutic use
  • Anesthesia
  • Animals
  • Blood Pressure / drug effects
  • Carbachol / pharmacology
  • Carbachol / therapeutic use
  • Cardiotonic Agents / pharmacology
  • Cardiotonic Agents / therapeutic use
  • Coronary Vessels / drug effects
  • Coronary Vessels / physiopathology
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Intracellular Signaling Peptides and Proteins
  • Ischemic Preconditioning, Myocardial / adverse effects
  • Ischemic Preconditioning, Myocardial / methods*
  • Lactates / blood
  • Male
  • Malondialdehyde / blood
  • Myocardial Infarction / blood
  • Myocardial Infarction / drug therapy
  • Myocardial Infarction / physiopathology
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Rats
  • Rats, Wistar
  • Tachycardia, Ventricular / drug therapy
  • Tachycardia, Ventricular / etiology
  • Tachycardia, Ventricular / physiopathology
  • Vasodilation / drug effects
  • Ventricular Premature Complexes / drug therapy
  • Ventricular Premature Complexes / etiology
  • Ventricular Premature Complexes / physiopathology
  • rho-Associated Kinases

Substances

  • Cardiotonic Agents
  • Intracellular Signaling Peptides and Proteins
  • Lactates
  • Malondialdehyde
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Carbachol
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • fasudil